Use of n-substituted (3,6-dihydro)-2h-1,2-oxazine...

Details Use of n-substituted (3,6-dihydro)-2h-1,2-oxazine... Use of n-substituted (3,6-dihydro)-2h-1,2-oxazine...

2001-07-30

2002-11-19

Raymond, Richard (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S230500, C544S063000

Reexamination Certificate

active

06482824

ABSTRACT:

This invention relates to novel chemical compounds and their use as pharmaceuticals.
It is known that excitatory neurotransmission in the mammalian central nervous system is primarily mediated by the amino acid, L-glutamate, acting on ionotropic and metabotropic receptors, and compounds that modify neurotransmission by interaction with these receptors are of interest for their potential use in the treatment of disorders of the central nervous system.
This invention relates to use of a compound of formula I
in which,
R
1
, R
2
and R
3
are independently hydrogen, (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
3
-C
10
)cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl(C
1
-C
6
)alkyl, unsubstituted or substituted aryl(C
2
-C
6
)alkenyl, halo, carboxy, (C
1
-C
6
)alkoxycarbonyl or —(CH
2
)
m
—OH, wherein m is 1, 2 or 3;
- - -
indicates a single or a double bond;
X and Y are each independently hydrogen, or X and Y together represent a bridge of the formula —(CH
2
)
n
—, where n is 1 or 2;
A
1
and A
2
are each independently an unsubstituted or substituted aryl;
Z is —CO—, —SO
2
— or —CH
2
—;
provided that, when Z is —CO—, A
1
is not 3,4,5-trimethoxyphenyl;
or a pharmaceutically-acceptable salt or ester thereof, for the manufacture of a medicament for the treatment of a condition indicating the administration of a selective mnGluR1 antagonist.
The present invention also provides a method of treating an animal, including a human, suffering from or susceptible to a condition indicating the administration of a selective mnGluR1 antagonist which comprises administering a compound as defined above or a pharmaceutically acceptable salt or ester thereof. The compounds of the invention have been found to be active in tests indicative of their use in the treatment of diseases of the central nervous system such as neurological diseases, for example, neurodegenerative diseases, and as antipsychotic, anticonvulsant, analgesic and anti-emetic agents.
In the above general formula, a (C
1
-C
6
)alkyl group can be straight or branched chain, such as, for example, methyl, ethyl, propyl, isopropyl, butyl and isobutyl, and is preferably methyl or ethyl. A (C
2
-C
6
)alkenyl group includes, for example, vinyl, prop-2-enyl, but-3-enyl, pent-4-enyl and. isopropenyl, and an alkenyl group can contain more than one double bond and, in addition, one or more triple bonds. A preferred alkenyl group is of the formula R′—CH═CH— where R′ is C
1
-C
4
alkyl.
A (C
3
-C
10
)cycloalkyl group is preferably, for example, cyclopropyl, cyclobutyl; cyclopentyl or cyclohexyl and these groups may optionally be substituted by one or two C
1
-C
4
alkyl, for example methyl, or ethyl substituents.
An unsubstituted or substituted aryl group includes aromatic and heteroaromatic rings, such as phenyl, napththalene, benzodioxan, thiophene, furan, pyrrole, imidazole, thiadiazole, pyridine, oxazole, benzofuran, indole and thiazole. An unsubstituted or substituted aryl(C
1
-C
6
)alkyl group is one such aryl group linked through an alkylene chain, for example, aryl- (CH
2
)
n
where n is 1 to 6, and a most preferred example is benzyl. An unsubstituted or substituted aryl(C
2
-C
6
)alkenyl is one such aryl group linked through an alkenylene chain derived from an alkenyl group as defined above, and preferably of the formula arly- (CH
2
)
n
CH═CH— where n is 1 to 4.
In the above general formula, when an aryl group is substituted, it is substituted with, for example, one or ore substituents, preferably 1 to 3 substituents, selected from (C
1
-C
6
)alkyl, hydroxy, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkylthio, halo, trifluoromethyl, cyano, nitro, amino, (C
1
-C
6
)alkylamino, (C
1
-C
6
)acylamino, —NHCOO—(C
1
-C
6
)alkyl, —NHSO
2
(C
1
-C
6
)alkyl (C
1
-C
6
)alkylsulphone or amide.
A halo includes for example fluoro, chloro and bromo, preferably fluoro or chloro.
A (C
1
-C
6
)alkoxy or a (C
1
-C
6
)alkylthio is an alkyl group linked to an oxygen or a sulphur atom, where the alkyl is as defined above. A (C
1
-C
6
)alkoxy or a (C
1
-C
6
)alkylthio group includes for example methoxy, ethoxy, methylthio or ethylthio.
A (C
1
-C
6
)alkylamino, is an alkyl group linked to a —NH— group, where the alkyl is as defined above. A (C
1
-C
6
)alkylamino group includes for example methylamino or ethylamino.
A (C
1
-C
6
)acylamino group is an alkyl group linked to an amide group, where the alkyl is as defined above, and is preferably of the formula R—CO—NH— where R is (C
1
-C
5
)alkyl.
A (C
1
-C
6
)acylamino group includes for example acetamido.
A (C
1
-C
6
)alkoxycarbonyl group is an alkoxy group linked to a carbonyl group, where the alkoxy group is as defined above. A (C
1
-C
6
)alkoxycarbonyl group includes for example methoxycarbonyl.
A —NHCOO—(C
1
-C
6
)alkyl, or a —NHSO
2
(C
1
-C
6
)alkyl group is an alkyl group linked to a group of the formula —NHCOO— or a —NHSO
2
—, where the alkyl is as defined above. A —NHCOO—(C
1
-C
6
)alkyl, or a —NHSO
2
(C
1
-C
6
)alkyl group includes for example methylcarbamoyl, or methylsulfonylamino.
A (C
1
-C
6
)alkylsulphone group is an alkyl group linked to a sulphone group, where the alkyl is as defined above. A (C
1
-C
6
)alkylsulphone group includes for example methylsulphone or ethylsulphone. It will be understood that
- - -
in formula (I) indicates that the bond can be either a single or a double bond. A preferred group of compounds according to formula (I) is one in which
- - -
indicates a double bond.
It is preferred that R
1
, R
2
and R
3
are each independently hydrogen, (C
1
-C
6
)alkyl, especially methyl or ethyl, carboxy or —(CH
2
)
m
—OH, wherein m is 1, 2 or 3.
It is also preferred that X and Y are each independently hydrogen.
It is especially preferred that A
1
is a phenyl substituted 1 to 3 times with a amino, (C
1
-C
6
)acylamino, especially acetamido or a —NHCOO—(C
1
-C
6
)alkyl, especially methylcarbamoyl. It is also preferred that A
2
is a phenyl substituted 1 to 3 times with a (C
1
-C
6
)alkoxy, especially ethoxy or ethoxy.
It is further preferred that Z is —SO
2
— or —CH
2
—, especially —SO
2
—.
Especially preferred compounds are of the formula
wherein,
R
1
and R
3
are each independently hydrogen, or (C
1
-C
6
)alkyl, especially methyl;
R
4
is amino, (C
1
-C
6
)acylamino, especially acetamide, or a —NHCOO—(C
1
-C
6
) alkyl, especially methylcarbamoyl;
R
5
is (C
1
-C
6
)alkoxy, especially methoxy or ethoxy, and
p and q are each independently 1 or 2, especially 1;
or a pharmaceutically-acceptable salt or ester thereof.
It will be appreciated that when P is other than one, then the R
5
substituents can be different. Similarly. when q is other than one, then the R
4
substituents can be different. It is further preferred that the R
4
substituent is in the 4 position of the phenyl ring.
Particularly useful compounds of invention are 2-(4-Acetamidobenzenesulphonyl)-3,6-dihydro-3, 5-dimethyl-6-(4-methoxyphenyl)-2H-1,2-oxazine, 2-(4-Acetamidobenzenesulphonyl)-3,6-dihydro-3,5-dimethyl-6-(4-ethoxyphenyl)-2H1,2-oxazine, and 3,6-dihydro-3,5-dimethyl-6-(4-ethoxyphenyl)-2-(4-methylcarbamoylbenzenesulphonyl)-2H-1,2-oxazine, or a pharmaceutically-acceptable salt or ester thereof.
It will also be understood that esters of the compounds of the invention can be prepared and such esters are included in the invention. They can be aliphatic or aromatic such as, for example, alkyl and phenolic esters. The most preferred esters are alkyl esters derived from C
1
-C
6
alkanols, especially methyl and ethyl esters.
It will also be understood that salts of the compounds of the invention can be prepared and such salts are included in the invention. They can be any of the well known acid addition salts. Acid addition salts are preferably the pharmaceutically-acceptable, non-toxic addition salts with suitable acids, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example glycollic, maleic, fumaric, malic, tartaric, citric, salicyclic or
o
-a

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